Mucosal innate immune cells regulate both gut homeostasis and intestinal inflammation

Abstract

Continuous exposure of intestinal mucosal surfaces to diverse microorganisms and their metabolites reflects the biological necessity for a multifaceted, integrated epithelial and immune cell-mediated regulatory system. The development and function of the host cells responsible for the barrier function of the intestinal surface (e.g., M cells, Paneth cells, goblet cells, and columnar epithelial cells) are strictly regulated through both positive and negative stimulation by the luminal microbiota. Stimulation by damage-associated molecular patterns and commensal bacteria-derived microbe-associated molecular patterns provokes the assembly of inflammasomes, which are involved in maintaining the integrity of the intestinal epithelium. Mucosal immune cells located beneath the epithelium play critical roles in regulating both the mucosal barrier and the relative composition of the luminal microbiota. Innate lymphoid cells and mast cells, in particular, orchestrate the mucosal regulatory system to create a mutually beneficial environment for both the host and the microbiota. Disruption of mucosal homeostasis causes intestinal inflammation such as that seen in inflammatory bowel disease. Here, we review the recent research on the biological interplay among the luminal microbiota, epithelial cells, and mucosal innate immune cells in both healthy and pathological conditions. Keywords: Epithelial cells r Homeostasis r Inflammation r Intestinal immunity r Mast cells Introduction to the function and homeostasis of the innate barrierThe intestinal mucosa is constantly being exposed to a wide range of biological stimuli, including commensal and pathogenic microorganisms and food materials. More than 10 14 microorganismsCorrespondence: Prof. Hiroshi Kiyono e-mail: kiyono@ims.u-tokyo.ac.jp reside in the intestinal lumen and provide nutrients for their host via enzymatic synthesis from food materials (reviewed in [1]). For example, microbial metabolites produced in the large intestine, such as short-chain fatty acids produced through polysaccharide fermentation, regulate the body's energy supply, the integrity of the epithelium, and the function of immune cells via the G protein-coupled receptors GPR41 and GPR43 (Fig. 1A, reviewed in [2] [6,7]). Deficiencies in any of the inflammasome components reduce the integrity of the epithelial barrier and increase susceptibility to intestinal inflammation [7]. This constant exposure of the epithelial surface to microbial components and products therefore requires sufficient epithelial regeneration and integrity to maintain a healthy mucosal barrier in the intestine. Directly below the epithelium, numerous innate and acquired immune cells create a homeostasis between the commensal flora of the intestine and the host immune system [8]. Among these immune cells, innate lymphoid cells (ILCs) and mast cells (MCs) are key players, which have multiple roles in maintaining homeostasis and innate immune surveillance to protect the host against invading parasitic worms (e.g., Nippostrongylus brasil...

Autoimmunity of Gastrointestinal Tract

“…Their localization in the follicles-associated epithelia of Payer's patches and/or isolated lymphoid follicles facilitates the induction of antigen-specific immune response within the mucous membrane. The last study showed that M cells are the entry point for intra-tissues commensal flora inducing IgA production in Peyer's patches [5,7]. The last equally important cells from epithelial layer are columnar epithelial cells forming very tight monolayer surface barrier, being regulated by the commensal microbiota.…”

“…NLRs are the group of intra-cellular pattern recognitions receptors (PRRs) involved in the recognition of many DAMPs and PAPMs (danger and pathogen-associated molecular patterns) in commensal and pathogenic microbiota. Inflammasome is a crucial structure for defence to pathogens but, from the other perspective, is involved in pathogenesis of autoinflammatory and autoimmune diseases following the prolonged inflammatory process [4][5][6]. The forming of inflammasome is not the only way of interaction between microbiota and immune systems.…”

“…Stimulated epithelial cells produce IL-25 directly reacting with myeloid cells present in mucous. The cascade of activation resulted in stimulation of ILC3 subpopulation of immune system and production of cytokines [5].…”

“…The goblet cells are also regulated partially through TLRs. The main role of goblet cells is production of mucins inhibiting the attachment of bacterial (commensal or pathogenic) to epithelial cells layer, particularly mucin-2, a main colonic gel-forming one [5]. The role of M cells is based on uptake of antigens from luminal spaces and induction of antigen-specific immune response.…”

“…ILCs produce IL-17A, IL-17F or IL-22. These groups differ in expression of receptors and, in consequence, play different regulatory roles in maintaining the homeostasis, induction of immune system response and inflammatory process [4,5]. Th17 lymphocytes, localized in lamina propria, produce large amounts of cytokines: IL-17A, IL-17F, IL-21 and IL-22 after stimulation with IL-6 and TGF-β.…”